Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation

• Published in: The Journal of experimental medicine Vol. 218; no. 3
• Main Authors: Yang, Kaiting, Hou, Yuzhu, Zhang, Yuan, Liang, Hua, Sharma, Anukriti, Zheng, Wenxin, Wang, Liangliang, Torres, Rolando, Tatebe, Ken, Chmura, Steven J, Pitroda, Sean P, Gilbert, Jack A, Fu, Yang-Xin, Weichselbaum, Ralph R
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.03.2021
• Subjects: Adaptive Immunity - drug effects; Administration, Oral; Animals; Antineoplastic Agents - pharmacology; Bacteria - drug effects; Brief Definitive Report; Butyrates - pharmacology; Gastrointestinal Microbiome - drug effects; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - microbiology; Immunity, Innate - drug effects; Interferon Type I - metabolism; Mice; Mice, Inbred C57BL; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Radiation, Ionizing; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor Immunology; Vancomycin - pharmacology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/JEM.20201915

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.